JPH024575B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a sustained release oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil coated with a PH-independent semipermeable film. 1-(2-tetrahydrofuryl)-5-fluorouracil (hereinafter abbreviated as THFU) is 5-
It is a masking compound for fluorouracil (hereinafter abbreviated as 5FU), and its own anticancer effect is said to be weak. Among anti-metabolite anticancer drugs, 5FU is a drug with excellent effects on solid cancers, but it has a short metabolic half-life and is rapidly metabolized to fluoro-β-alanine in the body, especially in the liver, so it is difficult to absorb in the body. Lack of sustainability. On the other hand, in the body, THFU is mainly metabolized in the liver and gradually converted to 5FU, so the concentration of 5FU in the blood lasts for a longer period of time than when 5FU itself is administered, and it also acts as a mask compound. It is also said to have fewer side effects on the digestive system compared to 5FU. For this reason, THFU is frequently used as an orally administrable anticancer drug, and is available in the form of uncoated granules, fine granules, or powders filled in gastric capsules, divided fine granules, granules, plain tablets, or suppositories. used in type. However, THFU is often administered continuously for a long period of time or in large doses, and in such cases, conventional formulations exhibit strong side effects on the digestive system and central system caused by THFU, and the concentration of 5FU in the blood is lower than that of THFU. Since it is proportional to the concentration, it has undesirable drawbacks such as the blood concentration that is given at the initial stage of administration, but the concentration quickly becomes low in proportion to the decrease in the THFU concentration. Incidentally, the action of antimetabolite anticancer drugs such as 5FU is not concentration dependent;
It is said to be time dependent. In other words, rather than the blood concentration becoming temporarily higher than necessary,
It is believed that the longer the blood concentration remains at a certain level, the more effective the treatment will be. In view of the above points, the present inventors aimed to maintain the effective blood concentration of 5FU for a long time, reduce the number of administrations and dosage, prevent excessive increases in the blood concentration of THFU and 5FU, and directly connect bulk powder to the intestinal mucosa. With the aim of preventing contact, improving and uniformizing bioavailability, and reducing side effects through the above improvements, we have conducted extensive research to improve the pharmaceutical formulation of the drawbacks of THFU.
The present invention has now been completed. That is, the present invention provides 1-(2-tetrahydrofuryl)-5 coated with a PH-independent semipermeable film.
-It is a sustained-release oral formulation containing fluorouracil as the active ingredient. Regarding sustained-release preparations, there are many known preparations that allow sustained release of the administered drug itself and sustained blood concentration. There are no known formulations that have made this possible. Next, the reason why the present invention uses a PH-independent semipermeable film will be described. It is known that THFU is hardly absorbed from the stomach and is well absorbed throughout the small intestine (Takashi Shimoyama et al.: Cancer and Chemotherapy Vol. 4, No. 2, 149-
158 pages, 1977). Therefore, it is possible to consider a method of using a suitable combination of PH-dependent films to achieve sustained and sustained drug release. However, elderly people and cancer patients have different gastric and intestinal fluids than normal people.
It is said that there are many people with PH, so-called achlorhydria, and weak digestive secretions, and the PH-dependent membrane cannot adequately control drug release and absorption. Furthermore, since the PH-dependent film itself dissolves, it is not possible to prevent the bulk powder from coming into direct contact with the membrane tube mucosa. For the above reasons, a PH-independent semipermeable film is used in the present invention. As a method for sustained release of THFU, all general sustained release methods can be applied, but it is preferable to use sugar, lactose, or crystals of the active ingredient as a core material, and coat this with a powder containing the active ingredient. A method of forming spherical granules and coating them with a PH-independent semipermeable film (so-called Spanseur formulation) is applied. Alternatively, a method may be used in which the extrusion granules are made into spherical granules using a marmerizer and a non-PH-dependent semipermeable coating is applied, or the granules are compressed together with a general excipient and a non-PH-dependent semipermeable coating is applied. Method of coating with a sexual film, non-
A method of microencapsulation with a PH-dependent poorly soluble film base may also be used. By these methods, preparations with the most uniform THFU release pattern can be obtained, but other known sustained release methods such as melt mixing with waxes or polymeric substances, or spray drying can also be used. may also be used. The PH-independent semipermeable film that provides sustained release is formed from a known poorly soluble substance. in this case,
A known water-soluble polymer substance may be added as appropriate. Known poorly soluble substances include, for example, higher hydrocarbons (e.g., paraffin, microcrystalline wax, ceresin), waxes (e.g., beeswax, carnauba wax, wood wax, spermaceti), and higher fatty acids (e.g., stearic acid). , palmitic acid, myristic acid), higher alcohols (e.g. stearyl alcohol, cetyl alcohol), higher fatty acid esters (e.g. myricyl balmitate, stearyl balmitate, stearyl myristate, lauryl laurate), higher fatty acid glycerides ( Examples, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monobalmitate, glyceryl dibalmitate,
glyceryl monooleate, glyceryl monolaurate, glyceryl tricaprate), hydrogenated hydrogenated oils (e.g., hydrogenated sesame oil, hydrogenated peanut oil, hydrogenated coconut oil), shellac, polyvinyl acetate, polyacrylic esters (e.g., polyvinyl acetate, ethyl acrylate,
(butyl polyacrylate), ethyl cellulose, etc. Known water-soluble polymer substances include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, and enteric film coating agents include hydroxypropylmethylcellulose. phthalate, cellulose acetate phthalate, methyl methacrylate, methacrylic acid copolymer, methyl acrylate, methacrylic acid copolymer, carboxymethylethyl cellulose, etc. Gastric soluble film coating agents include polyvinyl acetal, diethylaminoacetate, dimethylaminoethyl methacrylate, methyl methacrylate, etc. Examples include polymers of acrylic acid. These poorly soluble substances and water-soluble polymer substances are
They can be used alone or in combination of two or more as appropriate. Among these, combinations of higher hydrocarbons (for example, paraffin) and higher fatty acid glycerides, combinations of ethyl cellulose and polyethylene glycol, and combinations of ethyl cellulose and hydroxypropyl methylcellulose are particularly suitable. In addition, the sustained-release oral preparation containing THFU as an active ingredient coated with the non-PH-dependent semipermeable coating of the present invention may be coated with a conventionally known PH-dependent coating, such as a gastric soluble coating or an enteric coating. A sustained-release oral preparation containing THFU as the main drug can also be used in a mixed form. Next, we prototyped a sustained-release oral formulation of THFU coated with a non-PH-dependent semipermeable film with various drug release characteristics, and investigated its biological effects by filling it into gastric soluble capsules using beagle dogs. We will discuss the results of comparative observations using conventional oral preparations as a control. Table 1 shows commercially available oral preparations filled in gastric soluble capsules, Example 1 (6A), Example 2 (1.5A),
13(8B) shows the acute toxicity value (LD ₅₀ ) and autopsy findings in beagle dogs for the oral preparation of the present invention manufactured in 8B.

[Table] It is clear from Table 1 that the oral preparation of the present invention has significantly lower toxicity and less irritation of the intestinal mucosa than conventional oral preparations. In addition, by observing the pharmacokinetics using beagle dogs, it has been found that 20-70% of the total content is eluted in the first hour, preferably 30-60%, and the elution amount is gradually reduced in the USP dissolution test method. It has been found that a drug that releases the entire amount within 3 to 8 hours, particularly preferably 4 to 7 hours, has an excellent effect on maintaining the blood concentration of active 5FU. The present invention can be implemented in various embodiments, for example, spherical granules coated with non-PH-dependent semipermeable films having various drug release properties may be combined to form capsule-filled preparations, sachets, or controlled Tablets can be made into tablets with a non-PH-dependent semipermeable film having a controlled drug release rate, or microencapsulated with a non-PH-dependent, poorly soluble film base having a controlled drug release rate, and capsule filler if necessary. ,
Either a sachet or a compressed tablet can be used. According to the present invention, compared to conventional THFU formulations,
It has the excellent characteristics of low toxicity and minimal irritation to the intestinal mucosa, and by adjusting the release characteristics, it is possible to provide an oral preparation that has an excellent sustained effect on the blood concentration of active 5FU. Examples will be described below, but the present invention is not limited thereto. In addition, the "USP dissolution test method" and "blood concentration test using beagle dogs" in the examples were conducted according to the methods shown below. (1) "USP dissolution test method" Using coated granules or regular capsules of each example in an amount equivalent to 200 mg of THFU,
The test is carried out according to the method of USP (DISSOLUTION).The test liquid volume is 900ml.
The rotation speed of the basket is 100 revolutions per minute. The eluate was sampled over time, and the wavelength was 270n.
The absorbance is measured at the maximum wavelength of absorption near m, and the elution amount at each time point is calculated. (2) "Blood concentration test using beagle dogs" The coated granules or regular capsules of each example were administered to four beagle dogs each with an average weight of 9 kg.
Administer orally at 200mg/dog as THFU. After administration,
Blood is collected over time and immediately centrifuged to collect plasma. After adding 3 ml of physiological saline to 1 ml of the obtained plasma, 1N hydrochloric acid is added to adjust the pH to 2. Add 4 ml of chloroform to this, shake, centrifuge, and separate the chloroform layer. Add 4 ml of chloroform to the aqueous layer again and repeat the extraction operation. The chloroform layers are combined, dried up once, redissolved, and THFU is quantified using high performance liquid chromatography. On the other hand, the aqueous layer is subjected to pH adjustment and deproteinization, and then quantified by a bioassay method (inhibition circle measurement method using Staphylococcus aureus 209P). Example 1 While rolling 250 g of granulated sugar having 42 to 60 meshes in a centrifugal fluid coating granulator, 250 g of corn starch was granulated into spheres using 11 g of hydroxypropyl cellulose as a binder to produce nonpareils. Take 500g of nonpareil of 32 to 35 meshes, mix and crush 490g of THFU, 5g of talc, and 5g of light anhydrous silicic acid while rolling in a coating granulator, and powder coat and granulate using 18.75g of hydroxypropyl cellulose as a binder. did. 400 g of spherical granules thus obtained (THFU486
Ethanol in which 8.2 g of ethyl cellulose (manufactured by Dow Chemical Co., viscosity 100 cps) and 5.4 g of polyethylene glycol 4000 were dissolved and dispersed while rolling the mixture (containing mg/g) in a coating granulator.
The coating was applied by spraying 272 ml of methylene chloride (1:1 v/v) and drying with hot air (60° C.) (granules a). 400g of spherical granules obtained in the same manner (THFU486
17.5 g of ethyl cellulose (100 cps) and 11.7 g of polyethylene glycol 4000 were dissolved and dispersed in ethanol to methylene chloride (1:1 v/g) while rolling it in a coating granulator.
v) 608 ml was sprayed and coated while drying with hot air (60°C) (granules b). 400g of spherical granules obtained in the same manner (THFU486
Ethanol to methylene chloride (1:1 v/v) in which 4.5 g of ethyl cellulose (7 cps) and 1.9 g of polyethylene glycol 4000 were dissolved and dispersed while rolling (containing mg/g) in a coating granulator.
133 ml was sprayed and coated while drying with hot air (60°C) (granules c). Granules a, b, and c prepared as above are
They were mixed at a ratio of 10:25:65, and 220 mg (containing 100 mg as THFU) was filled into No. 2 capsules using a capsule filling machine (designated as 6A, the same applies hereinafter). FIG. 1 is a chart showing the time course of the dissolution rate of this oral preparation in simulated gastric fluid, simulated intestinal fluid, and water according to the USP dissolution test method. There was almost no difference in the elution rate between the liquids, indicating that they had uniform elution properties. Examples 2 to 15 Oral preparations having the film composition shown in Table 2 were prepared in the same manner as in Example 1.

[Table] Figures 2A and 2B are charts showing the dissolution rate of the oral preparations prepared in each Example using the USP dissolution test method and artificial intestinal fluid in comparison with that of regular capsules. Figure 2A shows examples 2 (1.5A), 3 (3A), 4 (3B), and 7.
(5A), 8 (5B), 10 (7A), and 11 (7B) are shown, and FIG. 2B shows Example 1 (6A), Example 5 (4A), 6 (4B), 9
(6B), 12 (8A), 13 (8B), 14 (10A), and 15 (10B) are shown for oral preparations. Figure 3 A and B show the THFU obtained when the coated granules and regular capsules of each example were administered to beagle dogs with an average weight of 9 kg as THFU at 200 mg/dog.
This is a chart showing the time course of the blood concentration of (average value of 4 animals in 1 group, quantified by high-speed liquid chromatography). FIGS. 4A and 4B are charts showing the time course of the blood concentration of active 5FU when the coated granules and regular capsules of each Example were administered as THFU at 200 mg/dog to beagle dogs with an average body weight of 9 kg. . (Average value of 4 animals per group, quantified by bioassay method). From these results, it can be seen that the oral preparations of the present invention all have a long drug elution time, and the blood concentration of 5FU is maintained at a high level for a long period of time. One that releases 66% of the active ingredient THFU in the first hour and the entire amount in three hours (3A), one that releases 39% in the initial hour and releases the entire amount in three hours (3B), 60% released in the first hour and the entire amount released in 4 hours (4A), in the first hour
One that releases 29% and releases the entire amount in 4 hours (4B), one that releases 50% in the first hour and releases the entire amount in 5 hours (5A), and 22% in the first hour.
and releases the entire amount in 5 hours (5B),
One that releases 43% in the first hour and the entire amount in six hours (6A), one that releases 20% in the initial hour and releases the entire amount in six hours (6B), and one that releases the entire amount in the first hour. The one that releases 38% in the first hour and releases the entire amount in 7 hours (7A), and the one that releases 32% in the first hour and releases the entire amount in 8 hours (8A), especially 4 to 12
It showed significantly higher blood concentration persistence of active 5FU over time compared to regular capsules. Among them, 4A, 5A, 6A, which were made to elute a relatively large amount (30 to 60%) of the active ingredient in the first hour, and gradually reduce the elution rate to release the entire amount over a period of 4 to 7 hours.
7A gave particularly favorable results, maintaining a blood concentration of 1.5 to 3 times the active 5FU concentration in the blood over a period of 4 to 12 hours compared to the blood active 5FU concentration obtained by conventional capsule administration. In addition, in order to examine changes in bioavailability, we took the 6A type preparation obtained in Example 1 and regular capsules as examples, and compared them in Figures 3B and 4B.
From this, the area under the blood concentration curve (AUC _0-12 ) from 0 to 12 hours was determined. The results are shown in Table 3.

[Table] Comparing the AUC _0-12 of the normal capsule and Example 1, there is almost no difference in THFU, which is slightly smaller in Example 1, but in terms of 5FU, Example 1 has a value of 1.85 compared to the normal capsule. It's doubled. That is, the formulation of the present invention, compared to conventional formulations,
Although the bioavailability of THFU is almost the same, the bioavailability of 5FU, a physiologically active substance, is 1.85 times higher. This is achieved by slow release of THFU.
This is surprising as the conversion rate of THFU to 5FU was approximately doubled. Those with a small initial elution amount and a uniform elution rate over a relatively long period of time (7A, 8B,
10B), and the one with a small amount of initial elution (10A), the active 5FU concentration at 1 to 4 hours was lower than that of regular capsules, but at 4 to 12 hours, it was almost the same. . On the other hand, the initial elution amount is large and the entire amount is released in a short time (1.5A)
No significant difference was observed in the normal capsule and blood concentration patterns.

[Brief explanation of drawings]

Figure 1 is a chart showing the time course of the dissolution rate in artificial gastric fluid, artificial intestinal fluid, and water according to the USP dissolution test method of Example 1 (6A), and Figures 2 A and B are the USP dissolution test method and artificial intestinal fluid. Figures 3A and B are graphs showing the dissolution rates of each Example and regular capsules, and the coated granules and regular capsules of each Example were administered to beagle dogs with an average body weight of 9 kg at 200 mg/day of THFU.
A chart showing the time course of the blood concentration of THFU when administered to dogs (average value of 4 dogs per group, quantified by high-speed liquid chromatography). Capsule for average weight 9
This is a chart showing the time course of the blood concentration of active 5FU when 200 mg/dog of THFU was administered to a Kg beagle dog (average value of 4 dogs per group, quantified by bioassay method).

Claims (1)

[Claims] 1 1-(2) coated with a PH-independent semipermeable film
-Tetrahydrofuryl)-5-Fluorouracil is a sustained-release oral preparation. 2. The sustained release oral preparation according to claim 1, which is a small spherical granule coated with a PH-independent semipermeable film. 3. The sustained release oral preparation according to claim 1, which is a tablet coated with a PH-independent semipermeable film. 4. The sustained-release oral preparation according to claim 1, which is a microcapsule coated with a PH-independent semipermeable film. 5. According to the USP dissolution test method, 20 to 70% of the active ingredient contained in the drug is released in the first hour, and the dissolution amount is gradually reduced to release the entire amount within 3 to 8 hours. 4. The sustained-release oral preparation according to any one of Item 4. 6 In the USP dissolution test method, claims 1 to 6 release 30 to 60% of the active ingredient in the first hour, gradually reduce the dissolution amount, and release the entire amount within 3 to 8 hours. 4. The sustained-release oral preparation according to any one of Item 4. 7. According to the USP dissolution test method, 30 to 60% of the active ingredient contained in the drug is released in the first hour, and the dissolution amount is gradually reduced to release the entire amount within 4 to 7 hours. 4. The sustained-release oral preparation according to any one of Item 4. 8. The sustained-release oral preparation according to any one of claims 1 to 7, wherein the PH-independent semipermeable film is formed of a complex containing ethyl cellulose. 9 Claim 1 in which the PH-independent semipermeable film is formed of a complex containing paraffin
The sustained release oral preparation according to any one of Items 7 to 7.